Scientists at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory and Stony2 Brook1 University have discovered a key difference in the way human cells and Mycobacterium tuberculosi(结核杆菌) bacteria, which cause TB, deliver unwanted proteins — marked with a "kiss of death" sequence — to their respective cellular3 recycling factories. This critical difference, described in a paper published online October 17, 2010, in the journal Nature Structural4 and Molecular5 Biology, may help scientists design drugs to disable the bacterial6 system while leaving normal human protein recycling centers intact. "With tuberculosis(肺结核)infecting a third of the world's population, primarily in developing countries, there is great need for new, effective TB treatments," said study co-author Huilin Li, a Brookhaven biophysicist and associate professor at SBU. "Our research seeks to understand the protein-recycling mechanism7 of TB bacteria, because it is one of the microbe's keys to survival in human cells. Targeting this system with small-molecule-based drugs could inhibit8 the bacteria and effectively treat TB."
The catch is that human cells have a similar protein-recycling system, essential for their survival, which could also be destroyed by inhibitory(禁止的,抑制的) drugs. "It's important to find differences between the species so we can target features unique to the bacterial system," Li said.
Li has previously9 looked at differences in the cellular structure known as a proteasome that chops up(切细,割断) the unwanted proteins. The current study examined the way proteins destined10 for degradation11 are recognized by the bacterial proteasome(蛋白酶体) before entering that structure.
Using beams of high-intensity x-rays at the Lab's ["http://www.nsls.bnl.gov/">National Synchrotron Light Source (NSLS), the scientists determined12 atomic-level structures of the portion of the bacterial proteasome that identifies the unwanted protein's "kiss of death" marker sequence — as well as structures of the marker sequence as it binds13 with the proteasome.
Based on the structures, the scientists describe a detailed14 mechanism by which coiled, tentacle-like arms protruding15(突出,伸出) from the proteasome identify the death sentence label, causing a series of protein-folding maneuvers16(军事演习) that pull the doomed17 protein into the degradation chamber18.
Importantly, this interaction between the bacterial proteasome and the marker sequence is unique to bacteria. Human cells use a different marker protein and a completely different mechanism for drawing doomed proteins into the proteasome. Thus the details of proteasome-substrate interaction revealed by the current study may provide highly specific targets for the development of new anti-tuberculosis therapies.